The present invention relates to biosensors for use in measuring concentration of analytes in biological fluids, and more particularly, to variations in the dose-response curves of such biosensors that occur during production.
Measuring the concentration of substances in biological fluids is important for diagnosis and treatment of many medical conditions. For example, the measurement of glucose in body fluids, such as blood, is crucial to the effective treatment of diabetes. Multiple methods are known for determining the concentration of analytes in a blood sample and generally fall into one of two categories: optical methods and electrochemical methods.
Optical methods generally involve spectroscopy to observe the spectrum shift in the fluid caused by concentration of the analyte, typically in conjunction with a reagent that produces a known color when combined with the analyte.
Electrochemical methods generally rely upon the correlation between a current (amperometry), a potential (potentiometry) or accumulated charge (coulometry) and the concentration of the analyte, typically in conjunction with a reagent that produces charge-carriers when combined with the analyte. See, for example, U.S. Pat. No. 4,233,029 to Columbus, U.S. Pat. No. 4,225,410 to Pace, U.S. Pat. No. 4,323,536 to Columbus, U.S. Pat. No. 4,008,448 to Muggli, U.S. Pat. No. 4,654,197 to Lilja et al., U.S. Pat. No. 5,108,564 to Szuminsky et al., U.S. Pat. No. 5,120,420 to Nankai et al., U.S. Pat. No. 5,128,015 to Szuminsky et al., U.S. Pat. No. 5,243,516 to White, U.S. Pat. No. 5,437,999 to Diebold et al., U.S. Pat. No. 5,288,636 to Pollmann et al., U.S. Pat. No. 5,628,890 to Carter et al., U.S. Pat. No. 5,682,884 to Hill et al., U.S. Pat. No. 5,727,548 to Hill et al., U.S. Pat. No. 5,997,817 to Crismore et al., U.S. Pat. No. 6,004,441 to Fujiwara et al., U.S. Pat. No. 4,919,770 to Priedel, et al., and U.S. Pat. No. 6,054,039 to Shieh, which are hereby incorporated in their entireties.
Electrochemical biosensors for conducting tests are typically provided as a disposable test strip having a reagent thereon that chemically reacts with the analyte of interest in the biological fluid. The test strip is mated to a test meter such that the test meter can measure the reaction between the analyte and the reagent in order to determine and display the concentration of the analyte to the user.
The response of an electrochemical biosensor to a potential step is largely governed by the Cottrell equation (F. G. Cottrell, Z. Physik. Chem., (1902)), Equation (1), below.
                              I          =                                                    nFAD                                  1                  2                                                                              π                                      1                    2                                                  ⁢                                  t                                      1                    2                                                                        ⁢            C                          ⁢                                  ⁢                  where          ⁢                                          ⁢          n          -                      number            ⁢                                                  ⁢            of            ⁢                                                  ⁢            electrons            ⁢                                                  ⁢            per            ⁢                                                  ⁢            molecule            ⁢                                                  ⁢            of            ⁢                                                  ⁢            analyte                          ⁢                                  ⁢                  F          -                      Faraday            ⁢                                                  ⁢            Constant                          ⁢                                  ⁢                  A          -                      working            ⁢                                                  ⁢            electrode            ⁢                                                  ⁢            area                          ⁢                                  ⁢                  D          -                      diffusion            ⁢                                                  ⁢            coefficient                          ⁢                                  ⁢                  t          -                      time            ⁢                                                  ⁢            after            ⁢                                                  ⁢            application            ⁢                                                  ⁢            of            ⁢                                                  ⁢            potential            ⁢                                                  ⁢            step                          ⁢                                  ⁢                  C          -                      Analyte            ⁢                                                  ⁢            concentration                                              (        1        )            It can be appreciated from Equation (1) that a change in the diffusion coefficient D will lead to a change in the dose-response of the sensor.
In many electrochemical sensors, dried films of chemistry are employed, typically covering the working electrode or the working and counter electrodes. These dried films contain enzymes that aid the exchange of electron(s) between the analyte and a mediator. A chemical process takes place when a liquid sample such as blood containing the analyte of interest hydrates the film. During this process, the film swells, analyte molecules diffuse into the film, and, with the aid of the analyte-specific enzymes present in the film, electron(s) are exchanged with the mediator molecules. In the presence of a specifically applied or controlled electrical potential, the mediator molecules diffuse to the electrode surface and are reduced or oxidized. Resulting current is then measured and then correlated using known techniques (e.g. amperometry, coulometry, potentiometry, voltammetry) to an amount, concentration or other desired characteristic of the analyte.
What is set forth as a simple diffusion coefficient D in Equation (1) actually (a) changes over time due to, e.g., swelling of the reagent; (b) is a sum of multiple diffusion processes (e.g., analyte diffusing from the fluid sample into the film to the enzyme, mediator diffusing from the reaction center to electrodes, etc.); and (c) may need to be adjusted to account for the kinetics of the enzyme reactions.
For the purposes of illustration, the following simple linear dose response equation (Equation (2)) can be used:C=kBCIBC+kIt  (2)
where
kBC, k are system specific coefficients
IBC is analyte independent blank current
It is current measured at time t
Or, in terms of current densities, introducing the working electrode area A:C=kBCAjBC+kAjt  (3)
where
jBC—analyte independent blank current density
jt—current density at time t
In the case of a very small blank current, Equation (3) can be simplified toC=kAjt  (4)
The analyte concentration C can be inaccurately estimated by an amount ΔC, which results from a change Δk that is in turn caused by, for example, variations in composition or thickness of the chemistry film that occur as part of an ongoing production process. This problem of inaccurately estimating analyte concentration can be appreciated from Equation (5), below.C+ΔC=(k+Δk)Ajt  (5)
Since variations in composition and thickness of the chemistry film used in these biosensors are important contributors to inaccuracy of the analyte concentration estimation, these parameters are typically controlled very well during the production process of an electrochemical biosensor. Nonetheless, in typical manufacturing processes, batches of only limited size can be produced based on, e.g., limited sized batches of raw materials that are used to produce the final biosensor product. In many cases, a new lot of biosensors might have a significantly different k, and a lot-to-lot variation as quantified in Equation (5) will thus result. Also, longer term trends, such as wear of machine parts or changes in raw material composition might also lead to a change of k, again resulting in an incorrect slope of the dose-response curve.
A standard method known in the art to address variations in the system specific coefficient k is to provide a lot specific coefficient 1-Δm that counteracts the change induced by Δk. This is represented in Equations (6) and (7), below:C=(k+Δk)(1−Δm)Ajt  (6)With
                              Δ          ⁢                                          ⁢          m                =                              Δ            ⁢                                                  ⁢            k                                k            +                          Δ              ⁢                                                          ⁢              k                                                          (        7        )            
Often, pairs of lot specific coefficients are provided, a first one of the coefficients describing the slope, similar to 1-Δm, and the second describing the intercept of a linear dose-response curve. Several lot specific coefficients or pairs of coefficients can be stored in the measurement instrument that is used with the biosensor and then selected by the user or automatically selected based on information contained on the biosensor. This approach has the drawback of requiring the meter to have sufficient memory to store several correction coefficients and in some cases also undesirably relies upon the user to select the correct lot information. It is known that users of these devices can fail to perform such required steps.
Alternatively, another common practice known in the art involves downloading such correction or calibration information into the test meter from an electronic read-only memory key (ROM key) that is inserted into a socket of the test meter. See, e.g., U.S. Pat. No. 5,366,609. Because this calibration data may only be accurate for a particular production lot of test strips, however, the user is usually asked to confirm that the lot number of the test strip currently in use matches the lot number for which the ROM key was programmed. This method undesirably requires production of several different ROM keys, and also relies on the user to change the ROM key when using a new vial of biosensors, which has been found does not always occur.
Yet another known method is to provide the value of the correction coefficients to the measurement instrument via a code key or via the disposable container (e.g., barcode). Another variant involves coding each biosensor itself with a barcode or other coding information. In this method, when the coded biosensor is inserted into the meter, the meter automatically applies the correct correction coefficients from several that are stored in its memory. While obviating the need for the user to take any affirmative steps to ensure that the proper correction coefficients are being used, this method requires that the meter have stored in it all correction coefficients that correspond to the various codes that can be provided on multiple different lots of biosensors, and of course requires lot specific coding of the biosensors.
Still another method involves controlling the biosensor production process so that only negligible lot-to-lot variations (Δk) occur, and if needed, those biosensors not meeting the implicit Δk≈0 requirement are rejected and discarded. This is often referred to as “universal code”. However, such methods are costly due to the large costs of meeting tight tolerances imposed in the first instance, and can be wasteful when large quantities of biosensors must be rejected and discarded for failing to meet those tolerances. Such wastefulness can be avoided by saving the biosensors of the rejected lots and providing them with another meter that requires a specific code input from the user, strip or vial, i.e. non-universal code meters. However, this requires that multiple lines of meter products are produced and distributed, which requires additional costs and expenses.
Because of the large amount of waste and difficulty in meeting tolerances, the “brute force” method just discussed is largely believed by those skilled in the art to be economically unworkable on a large production scale. Instead, those of skill in the art have come to accept the now conventional wisdom that lot to lot variations in the dose-response curve are inherent in the large-scale production of biosensors, and some type of calibration scheme like those discussed above must therefore be implemented after production in order to ensure an accurate estimation of the analyte concentration in a sample.
It would be desirable to provide another method for adjusting for variations in the dose-response curve of biosensors.